Retinoic acid signaling reduction recapitulates the effects of alcohol on embryo size

Abstract

Intrauterine growth restriction (IUGR) is commonly observed in human pregnancies and can result in severe clinical outcomes. IUGR is observed in Fetal Alcohol Syndrome (FAS) fetuses as a result of alcohol (ethanol) exposure during pregnancy. To further understand FAS, the severe form of Fetal Alcohol Spectrum Disorder, we performed an extensive quantitative analysis of the effects of ethanol on embryo size utilizing our Xenopus model. Ethanol-treated embryos exhibited size reduction along the anterior-posterior axis. This effect was evident primarily from the hindbrain caudally, while rostral regions appeared refractive to ethanol-induced size changes, also known as asymmetric IUGR. Interestingly, some embryo batches in addition to shortening from the hindbrain caudally also exhibited an alcohol-dependent reduction of the anterior head domain, known as symmetric IUGR. To study the connection between ethanol exposure and reduced retinoic acid levels we treated embryos with the retinaldehyde dehydrogenase inhibitors, DEAB and citral. Inhibition of retinoic acid biosynthesis recapitulated the growth defects induced by ethanol affecting mainly axial elongation from the hindbrain caudally.To study the competition between ethanol clearance and retinoic acid biosynthesis we demonstrated that, co-exposure to alcohol reduces the teratogenic effects of treatment with retinol (vitamin A), the retinoic acid precursor. These results further support the role of retinoic acid in the regulation of axial elongation.

Retinoic acid fluctuation activates an uneven, direction-dependent network-wide robustness response in early embryogenesis

“…We obtained similar results when we reduced the levels of RA by either blocking the biosynthesis (DEAB treatment) or by targeting this ligand for degradation (CYP26A1 overexpression). Also, multiple loss-of-function studies, described mild developmental malformations induced by RA signaling reduction as in the present study (Blumberg et al, 1997; Hollemann et al, 1998; Janesick et al, 2014; Koide et al, 2001; Kot-Leibovich and Fainsod, 2009; Shabtai et al, 2018; Sharpe and Goldstone, 1997; Shukrun et al, 2019). Therefore, increased or decreased RA levels in the physiological range result in mild developmental defects, suggesting the activation of compensatory mechanisms.…”

Preventing Ethanol-Induced Brain and Eye Morphology Defects Using Optogenetics

“…[11][12][13] Ethanol has also been shown to cause brain and eye defects by interfering with expression of key developmental transcription factor (Pax6, Otx2, etc. ), 19,50,74 retinoic acid signaling, [14][15][16] and reactive oxygen and nitrogen species signaling. [17][18][19][20] Thus, the effect of ethanol is likely to be multipronged, synergistically culminating in fetal alcohol syndrome-associated brain and eye defects.…”

“…4 Several molecular mechanisms have been shown to cause alcohol-associated teratogenic defects. [4][5][6] These mainly include ethanol-mediated dysfunction of ion channels and membrane voltage potentials, 5,7-10 metabotropic recep-tors (such as serotonin, cholinergic, and glutamate receptors), [11][12][13] retinoic acid signaling, [14][15][16] and reactive oxygen and nitrogen species signaling. [17][18][19][20] Finding repair strategies for such neural patterning defects is a crucial need in developmental medicine.…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Dietary deficiency of maternal vitamin A, exposure to drugs that interfere with vitamin A metabolism or signaling (ethanol, retinoid-based therapies) can cause severe congenital malformations (Collins & Mao, 1999;Petrelli, Bendelac, Hicks, & Fainsod, 2019;Shabtai, Bendelac, Jubran, Hirschberg, & Fainsod, 2018;Shukrun, Shabtai, Pillemer, & Fainsod, 2019;Wilson & Barch, 1949). Dietary deficiency of maternal vitamin A, exposure to drugs that interfere with vitamin A metabolism or signaling (ethanol, retinoid-based therapies) can cause severe congenital malformations (Collins & Mao, 1999;Petrelli, Bendelac, Hicks, & Fainsod, 2019;Shabtai, Bendelac, Jubran, Hirschberg, & Fainsod, 2018;Shukrun, Shabtai, Pillemer, & Fainsod, 2019;Wilson & Barch, 1949).…”

“…Therefore, maternal provision of adequate supplies of RA precursors in the form of retinol and REs or provitamin A carotenoids to the fetus is critical for its normal development and viability. Dietary deficiency of maternal vitamin A, exposure to drugs that interfere with vitamin A metabolism or signaling (ethanol, retinoid-based therapies) can cause severe congenital malformations (Collins & Mao, 1999;Petrelli, Bendelac, Hicks, & Fainsod, 2019;Shabtai, Bendelac, Jubran, Hirschberg, & Fainsod, 2018;Shukrun, Shabtai, Pillemer, & Fainsod, 2019;Wilson & Barch, 1949). Such retinoid-associated congenital defects can also be caused by mutations that affect genes involved in vitamin A metabolism, transport, or signaling (Chou et al, 2015;Pasutto et al, 2007;Pavan et al, 2009).…”